Abstract Hox genes are critical for maintaining the balance between self-renewal and differentiation of hematopoietic stem cells (HSCs). Although ectopic expression of the HoxB4 gene in bone marrow or embryonic stem cells (ESCs) leads to a dramatic expansion and long-term engraftment potential of HSCs, HoxB4 deficient mice exhibit only a mild reduction in progenitors and stem cells in fetal liver and bone marrow. In contrast, mice deficient in both HoxB3 and HoxB4 genes display severe hematopoietic defects with a marked decrease in HSC population indicating that other anterior HoxB genes may cooperate with HoxB4 to specify hematopoietic cell fate. It is important to understand underlying mechanisms by which the anterior HoxB genes are coordinately activated to confer HSC fate. The expression of Hox genes is regulated epigenetically by polycomb (PcG) and trithorax (TrxG) group regulators. We showed that recruitment of SETD1A to the HoxB4 locus governs its transcription activation and promotes HSC fate. Furthermore, we have identified and cloned a HoxB locus associated long intergenic noncoding RNA (lincRNA), HoxBlinc, which is expressed during early hematopoietic differentiation consistent with H3K4me3 patterns and anterior HoxB gene activation. Furthermore, HoxBlinc associates with the Setd1a HMT complex and controls the specification and differentiation of Flk1+ hemangioblasts. Thus, the data suggest that HoxBlinc RNA may play an important role in early hematopoiesis, at least in part by recruiting Setd1a HMT complexes onto the Hox genes thereby modulating Hox locus chromatin structure and organization. However, it remains unknown how HoxBlinc reprograms chromatin state to regulate anterior HoxB genes and hematopoietic specific transcription program and whether HoxBlinc plays a role in targeting histone modifying enzymes to these genes to initiate hematopoietic differentiation. Based on our preliminary data, we hypothesize that selective recruitment of the Setd1a HMT complex to the HoxB locus and coordination of anterior HoxB expression are mediated by HoxBlinc to specify the hematopoietic cell fate. In this proposal, we will examine the role of HoxBlinc in reprograming chromatin state and modulating anterior HoxB gene transcription. We will investigate underlying epigenetic mechanism by which HoxBlinc regulates early hematopoietic lineage commitment and differentiation. By finishing the proposed research, we expect a better understanding of molecular mechanism by which lincRNA and epigenetic regulators control early events of hematopoiesis.